PI: Brian Kobilka Structural Basis for Opioid Receptor Function Abstract of Research Plan The most powerful analgesic and addictive properties of opiate alkaloids are mediated by the OR. As the receptor primarily responsible for the effects of opium, the ?OR is one of the oldest drug targets within the pharmacopeia. Opioid receptors are highly versatile signaling molecules. Activation of the ?OR results in signaling through the heterotrimeric G protein Gi, resulting in analgesia and sedation as well as euphoria and physical dependence. The ?OR can also signal through arrestin, and this pathway has been attributed to adverse effects of opioid analgesics including tolerance, respiratory suppression, and constipation. The ?OR has been the subject of intense focus for drug-discovery efforts over the past century, with the identification of numerous ligands of varying efficacy. These drugs occupy a wide chemical spectrum, from small organic molecules to a variety of endogenous and synthetic peptides. Recently it has been shown that drugs may differ in their ability to promote activation of the Gi or arrestin pathways, a property referred to a ?bias?. It has recently been shown that Gi-biased drugs such as PZM21, identified during the initial funding period, may have better therapeutic profiles than non-biased agonists such as morphine. The goal of research funded by this award is to provide structural insights into biased signaling that will facilitate our ability to develop the next generation of opioid analgesics with fewer adverse effects and less addictive potential. Specific Aims for the next period of funding (described in more detail at the end of the Progress Report) Aim 1. Determine the structure of an opioid receptor in complex with Gi. Aim 2. Determine the structure of the OR bound to a G protein biased agonist. Aim 3. Determine the structure of an opioid receptor in complex with arrestin. Aim 4 . Characterize the effect of different ligands on OR structure and dynamics. Resource Sharing Plan: We will share all materials generated during the course of our studies. These will be distributed freely before or immediately after publication, and we will provide relevant protocols and published data upon request. Material transfers will be made with no more restrictive terms than in the Simple Letter Agreement (SLA) or the Uniform Biological Materials Transfer Agreement (UBMTA) and without reach through requirements. We will adhere to the NIH Grant Policy on Sharing of Unique Research Resources including the Sharing of Biomedical Research Resources Principles and Guidelines for Recipients of NIH Grants and Contracts issued in December, 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html?. Should any intellectual property arise which requires a patent, we will ensure that the technology (materials and data) remains widely available to the research community in accordance with the NIH Principles and Guidelines document. In addition, crystallographic coordinates and 3D electron microscopy maps will be deposited to the Protein Data Bank (PDB) and the Electron Microscopy Data Bank (EMDB), respectively.